N-dialkylaminoalkyl derivatives of alpha, beta-diarylalkanoamides and their salts



l atented Nov. fi l sfi N-DIALKYLAMINOALKYL DERIVATIVES OF a,fl-DIARYLALKANOAMIDES AND THEIR SALTS Carl Peter Krimmel, Mundelein, Ill., assignor to G. D. Searle & 00., Chicago, 111., a corporation of Illinois No Drawing. Application June 12, 1951, Serial No. 231,247

7 Claims. 1

The present invention is concerned with a new type of amide of a,/3-diarylalkanoic acid and salts thereof. In particular, it relates to N-dialkylaminoalkyl derivatives of a,fl-diarylalkanoamides of the structural formula salts thereof, wherein Ar and Ar are lower aryl radicals, A is a saturated, bivalent, lower aliphatic hydrocarbon radical containing at least two carbon atoms, R is a lower alkyl radical, and the radical NRR" is a member of the class consisting of dialkylamino radicals and saturated nitrogen-containing heterocyclic radicals attached to the alkylene radical A through a nitrogen in the heterocycle.

In the foregoing structural formula Ar and Ar may represent such lower aromatic hydrocarbon radicals as phenyl, tolyl, xylyl, naphthyl, methylnaphthyl, ethylnaphthyl, dimethylnaphthyl and the like. The radical A represents a bivalent, saturated, aliphatic hydrocarbon radical of from two to eight carbon atoms; this radical is derived from a straight-chain or branchedchain aliphatic hydrocarbon and includes radicals such as ethylene, propylene, butylene, amylene, or polymethylene radicals such as trimethylene, tetramethylene, pentamethylene, and hexamethylene. The radical R may represent such lower allryl groups as methyl, ethyl, propyl, butyl, amyl, hexyl, cyclopentyl and cyclohexl, wherein the propyl, butyl, amyl and hexyl groups may be either of the straight-chain or branchchain type. The radicals R and R may be of the same type as radical R. In addition the radical NRR" can also be a saturated nitrogencontaining heteromonocyclic group attached to the radical A through a nitrogen in the heteromonocycle; examples of such heteromonocycles are: N-piperidino, N-lupetidino, Napyrrolidino, N-morpholino, N-thiamorpholino, N'-alkyl-N- piperazino and like radicals.

2 thylmethyl chloride, dimethyl sulfate, diethyl sulfate, methyl benzene sulfonate, ethyl toluene sulfonate, ethylene chlorohydrin, propylene chlorohydrin, allyl bromide, methallyl bromide and crotyl bromide.

The object of this invention is to provide novel amides of a,fl-diarylalkanoic acids. Certain of these amides are valuable intermediates in organic synthesis. Others have been found to possess a number of useful pharmacodynamic properties. Thus the amides have a pronounced effect on the cardiovascular function and a potent diuretic eifect on renal excretory function.

My invention is disclosed in further detail in the following experimental part, which is set forth for the purpose of illustrating the invention and is in no way to be construed as limiting the invention in spirit or in scope. It will be apparent to those skilled in the art that many conventional modifications in methods, conditions, and materials can be adopted without departing therefrom. In each case temperatures are given uncorrected in degrees centigrade C.) and quantities in parts by Weight.

a,s-Diarylalkanoic acids The literature provides a number of useful procedures for the preparation of these acids. Thus saponification of the nitrile was employed by Plentl and Bogert (J. Am. Chem. Soc., vol. 63, pages 989 et seq.; 1941) for the preparation of a,13-diphenylbutyric acid and by Kohler (Am. Chem. J vol. 35, page 91; 1906) for the preparation of a,;3-diphenylvaleric acid. Ziegler et al. (Annalen der Chemie, vol. 4'73, page 35; 1929) prepared a,B-diphenylheptanoic acid by reacting stilbene with butyl lithium in ether and treating the reaction mixture with carbon dioxide. In certain instances, it is most advantageous to employ the method of Earl and Wilson, (J. Proc. Roy. Soc. N. S. Wales, vol. 65, pages 178 et seq.; 1932). By this method an a, 8-dibromoalkanoic acid of the type and the like in the presence of aluminum bromide.

a,,s-Diarylalkanoyl halides The acid halides of the aforementioned acids are prepared in the usual manner. Thus a mix- 3 ture of 440 parts of a,p-diphenylbutyric acid, 660 parts of thionyl chloride and 6400 parts of carbon tetrachloride is refluxed on the steam bath for three hours. The excess volatile reagents are removed under vacuum leaving awcrystalline yellow residue of a,p-diphenylbutyryl chloride which may be used without further purification or recrystallized once from petroleum ethersto yield a white powder, melting at about 137-141 C.

N-diallcylaminoallcyl-afldiarylallcanoamides These amides are prepared by reacting the above acid halides in an inert" anhydrous organic solvent with a dialkylaminoa'lkylamine of"the type HzN-A-NR'R" All symbols are defined as hereinabove.

Thus, the N-(B-diethylaminoethyl)-a,p-diphenylbutyramideis prepared {as follows. The

acid chloride from 4'00 parts 'of.a,pdiphenylbu tyric acid is -taken:up. .in'"700 parts of anhydrous ethyl ether." .Torthis. solution 2G0 parts of B-idiethylaminoethylamine and made alkaline With-,potassium;,l1ydro2dde.

"Thereleased basepis. jether extracted,- the extract, is dried coveruanhydrous rpotassiumrcarbo- 7 hate; filtered and the ether vremoved.ormthe steam bath. i The N.-(fidiethylaminoethyl).-a,}8- diphenylbutyramide. is .ohtaineduas. aasyrup which crystallizes on standing. 'It is converted to the hydrochloride .by dissolving) in "anhydrous (ether and adding. an equivalent: of a10%. hydro- .gen chlorideisopropanol..solution.. The precipitated hydrochloride is recrystallized from. bu- ,tanone .to' yield .white, .awater-t-soluble crystals melting at 159-161 C. r. The product has the N ('y dimethylaminopropyl) a,;8-dipheny1 butyramide is prepared bythe same procedure.

- It-is obtained as a crystalline residue-;by;aevap oration-of the ether @extract. .This residue ;is

r further purifiedby: recrystallization: from petroleum ether or by vacuum: distillation. =-:.In1the latter case it is distilledaat 221-229:C; and-0.5

mm. pressuremonncooli ng itsetsto a. solidxmelt- .ingA-atabout 95-:100 C. The hydrochloride; prepared. as above, consists of; white, wateresoluble crystals meltingat about:l71,'l;74 ,C. :Thissalt has the structural formula:

The N- (y-diethylaminopropyl) v flrdiphenylbu- 1 ,tyramideis, preparedbystirring aisolution' of; 250

parts of a,B-diphenylbutyryl chloride in 3500parts of anhydrous ether and adding slowly 125 parts of -diethylaminopropylamine. The tacky white precipitate is extracted: with water and the extract is separated and made alkaline. The ret leasecl -base is ether :extracted, the extract' dried a over anhydrous potassium carboriatey and the etherremoved -by di'sti'llation on the-steam bath.

The N- (y-diethylaminopropyl) -a,;8-diphenylbutyramide is obtainedas asyruplwhich crystallizes on standing. It may be rendered watersoluble "by "treatment-with 'an'equivalent'of a are slowly added I with stirring. The tacky whitePrecipitate is extracted with waterr andlthehextract is separated lHa H3 A mixtureof N (B-"diisopropylaminoethyl) M 3- ditolylisocaproaniides of f the structural formula CH(CH3)2 (CHmC H (|3H-(|3 H-C ONH CH2CH2'1 J crucial i.- cut N e (1 'lupetidino)ethyla,,8'-' diphenyl- -avaleraniide of the-structural formula:

The new'groupfof organic compounds con- 5 sisting of the N-dialkylamino'alkyl-afirdiarylal- *kanoamidesbfthe structural formula RI -R-.;G HaOHH: 0eNH-.AIN

, L 1 RH whereinAr. and Arriareilower aryl hydrocarbon .vcradicals containing 6.to 8,carbon atoms,.A.-is a Flower alkylene radical .containing..at least two 'carbon-iatoms, and.R,. R.' andR" are lower alkyl 75 tradicals.

2. The N-dialkylaminoalkyl (1,,8 diphenylalkanoamides of the structural formula RI RCH(]3 11-c ONHAN 6115 Calls R" wherein A is a lower alkylene radical containing at least two carbon atoms, and R, R and R" are lower alkyl radicals.

3. The N-dialkylaminoalkyl 11,5 diphenylbutyramides of the structural formula RI 0 135-0 13(05115 )CH( OHH)-0 ONHAN/ wherein A is a lower alkylene radical containing at least two carbon atoms, and R and R are lower alkyl radicals.

4. The N -diethylaminoalkyl a,B diphenylbutyramides of the structural formula wherein the radical A is a lower alkylene radical containing at least two carbon atoms.

5. N -(fi-cliethylaminoethyl) afi diphenylbutyramide.

6. N-( diethylaminopropyl) -a, 3-diphenylbutyramide.

7. N-'(" dimethylaminopropyl) -a,;8-diphenylbutyramide.

CARL PETER KRIMMEL.

References Cited in the file of this patent UNITED STATES PATENTS Name Date Miescher et a1 July 23, 1935 OTHER REFERENCES Number 

1. THE NEW GROUP OF ORGANIC COMPOUNDS CONSISTING OF THE N-DIALKYLAMINOALKYL-A,B-DIARYLALKANOAMIDES OF THE STRUCTURAL FORMULA 